Functional GLP-1R antibodies identified from a synthetic GPCR-focused library demonstrate potent blood glucose control.

G protein-coupled receptors (GPCRs) are a group of seven-transmembrane receptor proteins that have proven to be successful drug targets. Antibodies are becoming an increasingly promising modality to target these receptors due to their unique properties, such as exquisite specificity, long half-life, and fewer side effects, and their improved pharmacokinetic and pharmacodynamic profiles compared to peptides and small molecules, which results from their more favorable biodistribution. To date, there are only two US Food and Drug Administration-approved GPCR antibody drugs, namely erenumab and mogamulizumab, and this highlights the challenges encountered in identifying functional antibodies against GPCRs. Utilizing Twist's precision DNA writing technologies, we have created a GPCR-focused phage display library with 1 × 1010 diversity. Specifically, we mined endogenous GPCR binding ligand and peptide sequences and incorporated these binding motifs into the heavy chain complementarity-determining region 3 in a synthetic antibody library. Glucagon-like peptide-1 receptor (GLP-1 R) is a class B GPCR that acts as the receptor for the incretin GLP-1, which is released to regulate insulin levels in response to food intake. GLP-1 R agonists have been widely used to increase insulin secretion to lower blood glucose levels for the treatment of type 1 and type 2 diabetes, whereas GLP-1 R antagonists have applications in the treatment of severe hypoglycemia associated with bariatric surgery and hyperinsulinomic hypoglycemia. Here we present the discovery and creation of both antagonistic and agonistic GLP-1 R antibodies by panning this GPCR-focused phage display library on a GLP-1 R-overexpressing Chinese hamster ovary cell line and demonstrate their in vitro and in vivo functional activity.

Uso de inhibidores de la dipeptidil peptidasa 4 en pacientes con diabetes / No disponible

No disponible

Recomendaciones de las principales guías de práctica clínica / Recommendations of the main clinical practice guidelines

La aparición de nuevos fármacos para tratar la hiperglucemia en las personas con diabetes mellitus tipo 2 y los recientes estudios de seguridad cardiovascular de estas nuevas moléculas, conllevan la necesidad de actualización de las diferentes guías de práctica clínica y documentos de consenso sobre el abordaje y tratamiento de esta patología tan prevalente. En cuanto al tratamiento, metformina sigue siendo el fármaco de primera elección. Los fármacos inhibidores de la dipeptidil peptidasa 4 son fármacos antihiperglucemiantes orales con unas determinadas características que favorecen su uso en atención primaria. Entre otros aspectos, su bajo perfl de interacciones medicamentosas, el ser fácilmente combinables, la buena tolerancia, el efecto neutro sobre el peso y el bajo riesgo de hipo-glucemias, conducen a cierta comodidad de prescripción. Se han considerado los fármacos de elección en segundo escalón (y en primer escalón si está contraindicada o no se tolera la metformina) y podrían ver amenazada esta posición, en algunas situaciones concretas, con la aparición de nuevas familias de fármacos, como los inhibidores del cotrans-portador de sodio y glucosa y los análogos del receptor del péptido similar al glucagón tipo 1, algunas moléculas de las cuales han demostrado benefcios en la reducción de episodios cardiovasculares mayores y mortalidad. Es importante conocer el posicionamiento actual de los fármacos inhibidores de la dipep-tidil peptidasa 4 respecto al abordaje y tratamiento de la diabetes mellitus tipo 2, ya que han experimentado un aumento en la prescripción en atención primaria en los últimos años. (C) 2018 SEMERGEN. Publicado por Elsevier España, S.L.U. Todos los derechos reservados

The development of new drugs to treat hyperglycemia in persons with type 2 diabetes mellitus and recent cardiovascular safety studies of these new molecules have created the need to update the various clinical practice guidelines and consensus documents on the approach and treatment of this highly prevalent disease. Metformin continues to be the first-line drug. Dipeptidyl peptidase-4 inhibitors are oral lipid-lowering drugs with specific characteristics favouring their use in primary care. Among other characteristics, these drugs have few drug-drug interactions, can be easily combined with other drugs, are well tolerated, have a neutral effect on weight, and have a low risk of producing hypoglycaemic episodes, all of which encourages their prescrip-tion. Dipeptidyl peptidase-4 inhibitors are considered as second-line drugs (and as first-line drugs if metformin is contraindicated or poorly tolerated). In some specific situa-tions, this position could be threatened by the development of new drug families, such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 analogues, which have shown benefits in reducing major cardiovascular events and mortality. It is important to determine the current place of dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes mellitus, since they have been increasingly prescribed in primary care in the last few years

Seguridad de los inhibidores de la dipeptidil peptidasa 4 / Use of dipeptidyl peptidase-4 inhibitors in patients with diabetes

En el tratamiento de la diabetes mellitus tipo 2 se han introducido nuevos fármacos que han supuesto un avance en el abordaje fsiopatológico, con la posibilidad de actuar sobre los diferentes mecanismos implicados en la elevación de la glucemia y que permiten la individualización del tratamiento, como se recomienda en las guías y consensos al respecto. Al arsenal terapéutico de la diabetes se incorporó el grupo de las incretinas (2006), al que pertenecen los agonistas del receptor del péptido similar al glucagón 1 y los inhibidores de la enzima dipeptidil peptidasa 4, comercializados estos últimos en España en 2007, que actúan en el sistema incretínico del intestino reduciendo la glucemia, con efecto reductor o neutro en el peso y con bajo riesgo de hipoglucemias. Su introducción coincidió con la publicación de los controvertidos resultados de los estudios de control intensivo de la glucemia, que originó la normativa de la Food and Drug Administration (2008) que obliga a los nuevos fármacos hipoglucemiantes a demostrar su seguridad cardiovascular. La publicación de estos estudios ha evidenciado la seguridad cardiovascular y, en algunos de ellos, benefcios cardiovasculares y en la mortalidad, que están modifcando las guías y consensos sobre el tratamiento de la diabetes tipo 2. En este artículo se recogen las principales características sobre la seguridad y tolerancia de los inhibidores de la enzima dipeptidil peptidasa 4, a nivel farmacológico y cardiovascular, que es necesario conocer y actualizar en atención primaria, por su amplio uso y para un correcto abordaje de la terapia farmacológica en la diabetes tipo

New drugs have been added to the treatment of type 2 diabetes mellitus. These drugs have represented an advance in the physiopathological approach to the disease, with the possibility of acting on the different mechanisms involved in raised blood glucose levels and allowing treatment to be individualised, as recommended in clinical practice guide-lines and consensus documents. The incretins were added to the therapeutic arsenal of diabetes in 2006. This group in-cludes glucagon-like peptide-1 receptor antagonists and dipeptidyl peptidase-4 inhibitors (marketed in Spain in 2007), which act on the incretin system in the gut, reducing glycae-mia, with a decreasing or neutral effect on weight and with a low risk of hypoglycaemic episodes. Their introduction coincided with the publication of the controversial results of studies on intensive glycemic control, leading the Food and Drug Administration (2008) to require demonstration of the cardiovascular safety of new glucose-lowering drugs. The publication of subsequent studies has demonstrated cardiovascular safety and some have shown cardiovascular and survival benefits. These results are modifying the recommenda-tions of the clinical practice guidelines and consensus documents on the treatment of type 2 diabetes. The present article describes the main pharmacological and cardiovascular characteristics of the safety and tolerability of dipeptidyl peptidase-4 inhibitors, which need to be known and updated in primary care, given their wide prescription and the need for correct use of drug therapy in type 2 diabetes

Uso de inhibidores de la dipeptidil peptidasa 4 en pacientes con diabetes en situaciones especiales / Use of dipeptidyl peptidase-4 inhibitors in diabetic patients in special situations

Los inhibidores de la dipeptidil peptidasa 4 pertenecen al grupo de los derivados incretí-nicos y, por ello, presentan un mecanismo de acción específco. El efecto incretina permite evitar efectos secundarios de los fármacos clásicos (sulfonilureas) y aportar ventajas específcas para utilizarse en asociación y en situaciones especiales. Su escaso riesgo en la producción de hipoglucemia y de ganancia ponderal los hace útiles en asociación con otros antidiabéticos orales, incluso con insulinas, aunque con ello se pueda aumentar el riesgo de hipoglucemia de estas. Los grandes estudios de no inferioridad cardiovascular han señalado que su comportamiento no es inferior al placebo, aunque en algún fármaco (saxagliptina) haya aumentado el riesgo de hospitalización por insufciencia cardíaca. Estas ventajas cardiovasculares, incluso en la arteriopatía periférica, su buen comportamiento en la retinopatía diabética, junto con su escaso riesgo de hipoglucemia en la insu-fciencia renal, han hecho que sean fármacos de elección en el paciente anciano. Como factor limitante en su uso, dado el riesgo, aún no del todo valorado, no se recomiendan en pacientes con antecedentes de enfermedad pancreática o riesgo de tenerla, ni en niños, en la diabetes tipo 1, en adolescentes, en embarazadas o en mujeres lactantes. Cada una de estas situaciones especiales se desarrolla en el texto

Dipeptidyl peptidase-4 inhibitors form part of the group of incretin derivatives and conse-quently have a specific mechanism of action. The incretin effect avoids the adverse ef-fects of classic drugs (sulphonylureas) and provides specific benefits for their use in as-sociation with other drugs and in special situations. Because they have a low risk of pro-ducing hypoglycaemia or weight gain, these inhibitors are useful in combination with other oral antidiabetic drugs and even with insulin, although this latter combination may increase the risk of hypoglycaemia. Large studies of cardiovascular non-inferiority have reported that dipeptidyl peptidase-4 inhibitors are non-inferior to placebo, although one drug (saxagliptin) may increase the risk of hospital admission for heart failure. Because of these cardiovascular advantages, even in peripheral arterial disease, their usefulness in diabetic retinopathy, and their low risk of hypoglycaemia in renal insufficiency, dipeptidyl peptidase-4 inhibitors are the drugs of choice in elderly patients. Given the risk, although still not well defined, these drugs are not recommended in pa-tients with a history or risk of pancreatic disease, in children, in patients with type 1 diabetes, in adolescents, or in pregnant or breastfeeding women. Each of these special situ-ations is discussed in the present article

Control metabólico o reducción del riesgo vascular con los tratamientos actuales: ¿qué es prioritario? / Metabolic control or reduction of vascular risk with current treatments. What is the priority?

En el paciente con diabetes tipo 2, el control estricto de la glucemia previene o retrasa la aparición de complicaciones microvasculares. Por el contrario, sigue siendo debatido el efecto sobre las complicaciones macrovasculares y cuál es el papel del control glucémico precoz sobre la enfermedad cardiovascular subsiguiente. Aunque grandes ensayos clínicos aleatorizados no han mostrado un efecto claramente benefcioso del control intensivo a corto plazo, estudios posteriores de seguimiento de los participantes en estos ensayos sugieren un efecto cardiovascular favorable a largo plazo. Desde hace unos años, a raíz de las dudas sobre el aumento del riesgo de infarto de miocardio provocado por la rosiglitazona, las agencias reguladoras solicitan que, previa aprobación de una nueva molécula para el tratamiento de la hiperglucemia, el patrocinador demuestre que es segura desde el punto de vista cardiovascular. Los ensayos de seguridad cardiovascular publicados hasta el momento han evidenciado que los nuevos fármacos no incrementan el riesgo e, incluso, que algunas moléculas pueden proporcionar cierta protección cardiovascular. Ante estos hallazgos, ¿qué es prioritario al elegir el tratamiento hipoglucemiante: el control metabólico o la reducción del riesgo cardiovascular?. La palabra individualización ofrece la respuesta. No se puede situar el foco terapéutico únicamente en la seguridad cardiovascular dejando al margen las complicaciones micro-vasculares, causa de elevada morbimortalidad. Las personas con diabetes poco evolucionada y larga expectativa de vida se benefciarán de un control metabólico estricto. Los pacientes con diabetes y enfermedad cardiovascular establecida o elevado riesgo serán candidatos a un tratamiento que incluya fármacos que han demostrado un benefcio en este perfl de pacientes

In patients with type 2 diabetes, tight glycemic control prevents or delays the develop-ment of microvascular complications. In contrast, there is continued debate on the effect of macrovascular complications and the role of early glycaemic control on the ensuing cardiovascular disease. Although large randomised clinical trials have not shown a clearly beneficial effect of intensive control in the short term, subsequent follow-up studies of participants in these trials suggest a favourable cardiovascular effect in the long term. Due to doubts about the increased risk of myocardial infarction with rosiglitazone, for the last few years regulatory agencies have required sponsors to demonstrate the cardiovascular safety of new drugs before they can be approved for the treatment of hyperglycae-mia. The cardiovascular safety trials published to date have shown that the new drugs do not increase cardiovascular risk and that some molecules may even provide some cardiovascular protection. These findings raise the following question: what is the priority when selecting lipid-low-ering drugs - metabolic control or reduced cardiovascular risk?. The answer lies in the word individualisation. Treatment cannot focus solely on cardiovascular safety, without considering microvascular complications, which cause high morbidity and mortality. Patients with recent onset diabetes and long life expectancy will benefit from tight meta-bolic control. Patients with diabetes and established cardiovascular disease or at high risk are candidates for treatment that includes drugs with a demonstrated benefit in this pa-tient group

Is glucagon-like peptide-1 fully protected by the dipeptidyl peptidase 4 inhibitor sitagliptin when administered to patients with type 2 diabetes?

AIM: To evaluate the relationship between plasma dipeptidyl-peptidase 4 (DPP-4) activity and its protection of glucagon-like peptide-1 (GLP-1) using the DPP-4 inhibitor sitagliptin. METHODS: On four separate days, patients with type 2 diabetes (T2D) (n = 8; age: 59.9 ±10.8 [mean ±SD] years; body mass index [BMI]: 28.8 ±4.6 kg/m2 ; glycated haemoglobin A1c [HbA1c]: 43.1 ±0.5 mmol/mol [6.6% ±1.7%]) received a 380-minute continuous intravenous infusion of GLP-1 (1.0 pmol × kg bodyweight-1 × minutes-1 ) and a double-blind, single-dose oral administration of sitagliptin in doses of 0 (placebo), 25, 100 and 200 mg. RESULTS: Plasma DPP-4 activity decreased compared to baseline (placebo) with increasing doses of sitagliptin (P < .01), reaching a maximal inhibition with the 100 mg dose. Levels of intact GLP-1 increased with increasing doses of sitagliptin from placebo to 100 mg (area under curve [AUC] 7.2 [95%, CI; 12.1, 16.4] [placebo], 10.7 [16.1, 21.4] [25 mg], 11.7 [17.8, 23.6] [100 mg] nmol/L × 360 minutes [P < .01]), but no further increase in intact GLP-1 levels was observed with 200 mg of sitagliptin (11.5 [17.6, 23.4] nmol/L × 360 minutes) (P = .80). CONCLUSION: Our findings suggest that the sitagliptin dose of 100 mg is sufficient to inhibit both plasma and membrane-bound DPP-4 activity, presumably also leading to complete protection of endogenous GLP-1 in patients with T2D.

Exenatide effects on gastric emptying rate and the glucose rate of appearance in plasma: A quantitative assessment using an integrative systems pharmacology model.

This study aimed to quantify the effect of the immediate release (IR) of exenatide, a short-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA), on gastric emptying rate (GER) and the glucose rate of appearance (GluRA), and evaluate the influence of drug characteristics and food-related factors on postprandial plasma glucose (PPG) stabilization under GLP-1RA treatment. A quantitative systems pharmacology (QSP) approach was used, and the proposed model was based on data from published sources including: (1) GLP-1 and exenatide plasma concentration-time profiles; (2) GER estimates under placebo, GLP-1 or exenatide IR dosing; and (3) GluRA measurements upon food intake. According to the model's predictions, the recommended twice-daily 5- and 10-µg exenatide IR treatment is associated with GluRA flattening after morning and evening meals (48%-49%), whereas the midday GluRA peak is affected to a lesser degree (5%-30%) due to lower plasma drug concentrations. This effect was dose-dependent and influenced by food carbohydrate content, but not by the lag time between exenatide injection and meal ingestion. Hence, GER inhibition by exenatide IR represents an important additional mechanism of its effect on PPG.

Efficacy and tolerability of the new autoinjected suspension of exenatide once weekly versus exenatide twice daily in patients with type 2 diabetes.

AIMS: To simplify administration of aqueous exenatide once weekly, which requires reconstitution, the exenatide microspheres have been reformulated in a ready-to-use autoinjector with a Miglyol diluent (exenatide QWS-AI). This study compared the efficacy and safety of exenatide QWS-AI with the first-in-class glucagon-like peptide-1 receptor agonist exenatide twice daily (BID). MATERIALS AND METHODS: This randomized, open-label, controlled study in patients with type 2 diabetes using diet and exercise or taking stable oral glucose-lowering medication randomized patients 3:2 to either exenatide QWS-AI (2 mg) or exenatide BID (10 µg) for 28 weeks. The primary outcome was the 28-week change in glycated haemoglobin (HbA1c). A subset of patients completed a standardized meal test for postprandial and pharmacokinetic assessments. RESULTS: A total of 375 patients (mean HbA1c, 8.5% [69 mmol/mol]; body mass index, 33.2 kg/m2 ; diabetes duration, 8.5 years) received either exenatide QWS-AI (n = 229) or exenatide BID (n = 146); HbA1c was reduced by -1.4% and -1.0%, respectively (least-squares mean difference, -0.37%; P = .0072). More patients achieved HbA1c <7.0% with exenatide QWS-AI (49.3%) than with exenatide BID (43.2%; P = .225). Body weight was reduced in both groups (P = .37 for difference). Gastrointestinal adverse events (AEs) were reported in 22.7% (exenatide QWS-AI) and 35.6% (exenatide BID) of patients; fewer patients in the exenatide QWS-AI group withdrew because of AEs than in the exenatide BID group. Minor hypoglycaemia occurred most often with concomitant sulfonylurea use. CONCLUSIONS: Exenatide QWS-AI was associated with a greater reduction in HbA1c, similar weight loss and a favorable gastrointestinal AE profile compared with exenatide BID.

Preclinical characterization of 55P0251, a novel compound that amplifies glucose-stimulated insulin secretion and counteracts hyperglycaemia in rodents.

AIMS: 55P0251 is a novel compound with blood glucose lowering activity in mice, which has been developed from a molecular backbone structure found in herbal remedies. We here report its basic pharmacological attributes and initial progress in unmasking the mode of action. MATERIALS AND METHODS: Pharmacokinetic properties of 55P0251 were portrayed in several species. First efforts to elucidate the glucose lowering mechanism in rodents included numerous experimental protocols dealing with glucose tolerance, insulin secretion from isolated pancreatic islets and comparison to established drugs. RESULTS: A single oral dose of 55P0251 improved glucose tolerance in mice with an ED50 between 1.5 and 2 mg/kg (reductions in areas under the curve, 1 mg/kg, -18%; 5 mg/kg, -30%; 27 mg/kg, -47%). Pharmacokinetic studies revealed attractive attributes, including a plasma half-life of approximately 3 hours and a bioavailability of approximately 58% in rats. 55P0251 amplified glucose stimulated insulin release from isolated mouse islets and improved glucose tolerance via increased insulin secretion in rats (increase in area under the insulin curve, +184%). Unlike sulfonylureas and glinides, 55P0251 hardly stimulated insulin release under basal conditions and did not induce hypoglycaemia in vivo, but it amplified the secretory response to glucose and other insulinotropic stimuli (KCl, glucagon-like peptide-1). Comparison to established anti-diabetic agents and examination of interaction with molecular targets (KATP channel, dipeptidyl peptidase-4, glucagon-like peptide-1 receptor) excluded molecular mechanisms addressed by presently marketed drugs. CONCLUSIONS: 55P0251 is a novel compound that potently counteracts hyperglycaemia in rodents via amplification of glucose-stimulated insulin release.

Pharmacogenomics in type 2 diabetes: oral antidiabetic drugs.

Type 2 diabetes mellitus (T2DM) is a fast progressing disease reaching pandemic proportions. T2DM is specifically harmful because of its severe secondary complications. In the course of the disease, most patients require treatment with oral antidiabetic drugs (OADs), for which a relatively large number of different options are available. The growing number of individuals affected by T2DM as well as marked interindividual differences in the response to treatment call for individualized therapeutic regimens that can maximize treatment efficacy and thus reduce side effects and costs. A large number of genetic polymorphisms have been described affecting the response to treatment with OADs; in this review, we summarize the most recent advances in this area of research. Extensive evidence exists for polymorphisms affecting pharmacokinetics and pharmacodynamics of biguanides and sulfonylureas. Data on incretin-based medications as well as the new class of sodium/glucose cotransporter 2 (SGLT2) inhibitors are just starting to emerge. With diabetes being a known comorbidity of several psychiatric disorders, we also review genetic polymorphisms possibly responsible for a common treatment response in both conditions. For all drug classes reviewed here, large prospective trials are necessary in order to consolidate the existing evidence and derive treatment schemes based on individual genetic traits.

Efecto de las terapias incretínicas comparadas con pioglitazona y gliclazida en la esteatosis hepática no alcohólica de los pacientes diabéticos no controlados solo con metformina: estudio observacional piloto / Effect of incretin therapies compared to pioglitazone and gliclazide in non-alcoholic fatty liver disease in diabetic patients not controlled on metformin alone: An observational, pilot study

Objetivo: Comparar el efecto de diferentes hipoglucemiantes en indicadores analíticos y ecográficos de la esteatosis hepática no alcohólica (EHNA) en pacientes con diabetes tipo 2 no controlados solo con metformina. Métodos: Estudio prospectivo de pacientes diabéticos tratados con metformina, en combinación con gliclazida, pioglitazona, sitagliptina, exenatida o liraglutida. En el momento basal y a los 6 meses la EHNA fue valorada por ecografía abdominal y se calculó el índice de fibrosis de la EHNA. Resultados: Cincuenta y ocho pacientes completaron los 6 meses de seguimiento: 15 recibieron gliclazida, 13 pioglitazona, 15 sitagliptina, 7 exenatida y 8 liraglutida. La EHNA afectó basalmente al 57,8% de los casos y su evolución ecográfica varió dependiendo de la evolución del peso (p = 0,009) y de la cintura (p = 0,012). Los porcentajes de sujetos que experimentaron una mejoría ecográfica en los diferentes grupos de tratamiento fueron: 33,3% con gliclazida, 37,5% con pioglitazona, 45,5% con sitagliptina, 80% con exenatida y 33% con liraglutida (p = 0,28). Conclusiones: La evolución ecográfica cualitativa de la EHNA en el paciente diabético tratado con metformina en combinación con otros hipoglucemiantes está vinculada a la evolución del peso y del perímetro de cintura. Son precisos ensayos clínicos de larga duración para evaluar si las terapias incretínicas se asocian a mejores resultados hepáticos que otras terapias hipoglucemiantes (AU)

Aim: To compare the effect of different hypoglycemic drugs on laboratory and ultrasonographic markers of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes not controlled on metformin alone. Methods: Prospective study of diabetic patients treated with metformin in combination with gliclazide, pioglitazone, sitagliptin, exenatide, or liraglutide. NAFLD was assessed by abdominal ultrasound and NAFLD fibrosis score was calculated at baseline and 6 months. Results: Fifty-eight patients completed 6 months of follow-up: 15 received gliclazide, 13 pioglitazone, 15 sitagliptin, 7 exenatide, and 8 liraglutide. NAFLD affected 57.8% of patients at baseline, and its ultrasonographic course varied depending on changes in weight (P = .009) and waist circumference (P = .012). The proportions of patients who experienced ultrasonographic improvement in the different treatment groups were: 33.3% with gliclazide, 37.5% with pioglitazone, 45.5% with sitagliptin, 80% with exenatide, and 33% with liraglutide (P = .28). Conclusions: Qualitative ultrasonographic NAFLD improvement in diabetic patients treated with metformin in combination with other hypoglycemic drugs is associated to change over time in weight and waist circumference. Long-term clinical trials are needed to assess whether incretin therapies result in better liver outcomes than other hypoglycemic therapies (AU)

Exposure-response analyses of liraglutide 3.0 mg for weight management.

AIMS: Liraglutide 3.0 mg, an acylated GLP-1 analogue approved for weight management, lowers body weight through decreased energy intake. We conducted exposure-response analyses to provide important information on individual responses to given drug doses, reflecting inter-individual variations in drug metabolism, absorption and excretion. METHODS: We report efficacy and safety responses across a wide range of exposure levels, using data from one phase II (liraglutide doses 1.2, 1.8, 2.4 and 3.0 mg), and two phase IIIa [SCALE Obesity and Prediabetes (3.0 mg); SCALE Diabetes (1.8; 3.0 mg)] randomized, placebo-controlled trials (n = 4372). RESULTS: There was a clear exposure-weight loss response. Weight loss increased with greater exposure and appeared to level off at the highest exposures associated with liraglutide 3.0 mg in most individuals, but did not fully plateau in men. In individuals with overweight/obesity and comorbid type 2 diabetes, there was a clear exposure-glycated haemoglobin (HbA1c) relationship. HbA1c reduction increased with higher plasma liraglutide concentration (plateauing at ∼21 nM); however, for individuals with baseline HbA1c >8.5%, HbA1c reduction did not fully plateau. No exposure-response relationship was identified for any safety outcome, with the exception of gastrointestinal adverse events (AEs). Individuals with gallbladder AEs, acute pancreatitis or malignant/breast/benign colorectal neoplasms did not have higher liraglutide exposure compared with the overall population. CONCLUSIONS: These analyses support the use of liraglutide 3.0 mg for weight management in all subgroups investigated; weight loss increased with higher drug exposure, with no concomitant deterioration in safety/tolerability besides previously known gastrointestinal side effects.

dulaglutide (Trulicity°) weekly in type 2 diabetes: Cardiovascular reactions should be better documented.

In four trials including a total of more than 3000 patients, dulaglutide reduced the HbA1c concentration as effectively as other GLP-1 analogues when added to other hypoglycaemic drugs. The long elimination half-life of dulaglutide can make management of adverse effects and drug interactions more difficult. More data are needed on possible cardiac adverse effects.

Metformin and other antidiabetic agents in renal failure patients.

This review mainly focuses on metformin, and considers oral antidiabetic therapy in kidney transplant patients and the potential benefits and risks of antidiabetic agents other than metformin in patients with chronic kidney disease (CKD). In view of the debate concerning lactic acidosis associated with metformin, this review tries to solve a paradox: metformin should be prescribed more widely because of its beneficial effects, but also less widely because of the increasing prevalence of contraindications to metformin, such as reduced renal function. Lactic acidosis appears either as part of a number of clinical syndromes (i.e., unrelated to metformin), induced by metformin (involving an analysis of the drug's pharmacokinetics and mechanisms of action), or associated with metformin (a more complex situation, as lactic acidosis in a metformin-treated patient is not necessarily accompanied by metformin accumulation, nor does metformin accumulation necessarily lead to lactic acidosis). A critical analysis of guidelines and literature data on metformin therapy in patients with CKD is presented. Following the present focus on metformin, new paradoxical issues can be drawn up, in particular: (i) metformin is rarely the sole cause of lactic acidosis; (ii) lactic acidosis in patients receiving metformin therapy is erroneously still considered a single medical entity, as several different scenarios can be defined, with contrasting prognoses. The prognosis for severe lactic acidosis seems even better in metformin-treated patients than in non-metformin users.

Pharmacokinetics and clinical use of incretin-based therapies in patients with chronic kidney disease and type 2 diabetes.

The prevalence of chronic kidney disease (CKD) of stages 3-5 (glomerular filtration rate [GFR] <60 mL/min) is about 25-30 % in patients with type 2 diabetes mellitus (T2DM). While most oral antidiabetic agents have limitations in patients with CKD, incretin-based therapies are increasingly used for the management of T2DM. This review analyses (1) the influence of CKD on the pharmacokinetics of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists; and (2) the efficacy/safety profile of these agents in clinical practice when prescribed in patients with both T2DM and CKD. Most DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin) are predominantly excreted by the kidneys. Thereby, pharmacokinetic studies showed that total exposure to the drug is increased in proportion to the decline of GFR, leading to recommendations for appropriate dose reductions according to the severity of CKD. In these conditions, clinical studies reported a good efficacy and safety profile in patients with CKD. In contrast, linagliptin is eliminated by a predominantly hepatobiliary route. As a pharmacokinetic study showed only minimal influence of decreased GFR on total exposure, no dose adjustment of linagliptin is required in the case of CKD. The experience with GLP-1 receptor agonists in patients with CKD is more limited. Exenatide is eliminated by renal mechanisms and should not be given in patients with severe CKD. Liraglutide is not eliminated by the kidney, but it should be used with caution because of the limited experience in patients with CKD. Only limited pharmacokinetic data are also available for lixisenatide, exenatide long-acting release (LAR) and other once-weekly GLP-1 receptor agonists in current development. Several case reports of acute renal failure have been described with GLP-1 receptor agonists, probably triggered by dehydration resulting from gastrointestinal adverse events. However, increasing GLP-1 may also exert favourable renal effects that could contribute to reducing the risk of diabetic nephropathy. In conclusion, the already large reassuring experience with DPP-4 inhibitors in patients with CKD offers new opportunities to the clinician, whereas more caution is required with GLP-1 receptor agonists because of the limited experience in this population.

Evaluation of PEGylated exendin-4 released from poly (lactic-co-glycolic acid) microspheres for antidiabetic therapy.

Peptide-based therapies have the potential to induce antibody formation if the molecules differ from a native human peptide. Several reports have disclosed the occurrence of antibody generation in a patient treated with exenatide. The immune response can be problematic from a clinical stand point, particularly if the antibodies neutralize the efficacy of the biotherapeutic agent or cause a general immune reaction. To overcome this limit, PEGylated exendin-4 analogs were designed and examined for metabolic stability and biological activity. To develop an extended release delivery system for exendin-4 for the safe and effective delivery of bioactive exendin-4 without peptide acylation and immunogenicity, PEGylated exendin-4 was encapsulated into poly (lactic-co-glycolic acid) (PLGA) microspheres by w/o/w double emulsion solvent evaporation method. Peptide-loaded microspheres were characterized in terms of morphology, particle diameter, and peptide encapsulation efficiency. Then, the release profile of the peptide from PLGA microspheres and the acylated products from PLGA polymer degradation was determined. The results obtained showed that the stability of exendin-4 was greatly improved by PEGylation. Moreover, eliminated acylation during PLGA polymer degradation in vitro and reduced immunogenicity in vivo were observed. The findings demonstrate that PEGylated exendin-4-loaded microspheres may be a safe and biocompatible system for clinical development.

Clinical pharmacology of albiglutide, a GLP-1 receptor agonist.

UNLABELLED: Albiglutide is a glucagon-like peptide-1 analogue composed of tandem copies of modified human glucagon-like peptide-1 (7-36) coupled to recombinant human albumin that is approved in adults for the treatment of type 2 diabetes mellitus. After subcutaneous administration, albiglutide is likely primarily absorbed via the lymphatic circulation, with maximum concentrations being reached in 3 to 5 days; steady-state exposures are achieved following approximately 4 to 5 weeks of once-weekly administration. The elimination half-life of albiglutide is approximately 5 days. Clearance of albiglutide is 67 mL/h with between-subject variability of 34.9%; no covariates have been identified that would require dose adjustment of albiglutide. Albiglutide lowers the fasting plasma glucose and reduces postprandial glucose excursions. In addition, ß-cell secretion is enhanced by albiglutide during hyperglycemia, whereas secretion is suppressed during hypoglycemia; α-cell response to hypoglycemia is not impaired by albiglutide. Albiglutide does not prolong the corrected QT interval but has a modest effect on heart rate in patients with type 2 diabetes mellitus. Dose adjustment is not suggested in patients with renal impairment, but experience in patients with severe renal impairment is very limited, and it is recommended that albiglutide be used with care in such patients due to an increased frequency of diarrhea, nausea, and vomiting. No clinically relevant drug interactions have been observed in clinical trials. TRIAL REGISTRATION: NCT00938158, NCT01406262, NCT00537719, NCT01077505, NCT01147731, NCT01147718, NCT01147692, NCT00354536, NCT00394030, NCT00530309, NCT01357889, NCT00518115, NCT01098461, NCT01475734, NCT00849017, NCT00838916, NCT00839527, NCT01098539.

Modulación del efecto incretina en el tratamiento de la diabetes / Modulation of the incretin effect in the treatment of diabetes

La modulación del efecto incretina ha abierto una nueva estrategia en el tratamiento de la diabetes mellitus tipo 2 (DM2). La potenciación de este mecanismo fisiológico se ha conseguido hasta la fecha por dos vías. De una parte, la inhibición farmacológica de la enzima que degrada fisiológicamente a péptido similar al glucagón-1 (GLP-1), la dipeptidil peptidasa-4 (DPP-4). Por otra, el desarrollo de moléculas agonistas del receptor de GLP-1 (arGLP-1) resistentes a la acción de la DPP-4. Distintos ensayos clínicos han demostrado la mayor eficacia clínica de los arGLP-1, lo cual parecería ligado al alcance de mayores niveles circulantes de GLP-1. En contrapartida, esta parece ser la base también de la mayor tasa de efectos adversos asociados al tratamiento con arGLP-1 en comparación con la inhibición de DPP-4. La valoración de estas y otras características diferenciadoras de ambas familias de fármacos deberá marcar nuestra elección en el tratamiento personalizado de la hiperglucemia en el paciente con DM2 (AU)

Modulation of the incretin effect has opened up a new strategy in the treatment of diabetes mellitus type 2 (DM2). To date, this physiological mechanism has been boosted in two ways: firstly, by pharmacological inhibition of the enzyme that physiologically degrades glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP4); secondly, through the development of GLP-1 agonists (GLP-1a) that are resistant to the action of DPP-4. Several clinical trials have shown the clinical superiority of GLPa, which seems to be linked to higher circulating levels of GLP-1. On the other hand, this higher efficacy also seems to be associated with the higher rate of adverse effects associated with aGLP-1 therapy compared with DPP-4 inhibition. These and other differentiating characteristics of the two drug families will determine the choice of drug therapy in the personalized treatment of hyperglycemia in patients with DM2 (AU)